Injection and non-injection drug use and abuse remain significant cofactors for HIV infection and transmission. The drugs of abuse such as cocaine has also been implicated in HIV-1-associated pathogenesis e.g. HAD, HAND. It has become clear that drugs of abuse, including cocaine can modify both cellular epigenetic and signaling pathways, which ultimately modulate the expression of several cellular genes. Therefore, it would not be surprising if the gene expressions of integrated human immunodeficiency virus (HIV) provirus's are also influenced with this type of stimuli. Although, HIV gene expression by cocaine until now is mainly attributed to up regulation of several chemokines, cytokines, signaling pathways and some of viral proteins (e.g. Tat and Env), however, the molecular mechanism such as changes in epigenetic and signaling pathways by drugs of abuse could explain better the continuous induction of several genes even after removal of drug of abuse, which is normally the case. In order to develop better understanding of the complex interplay between drugs of abuse and HIV replication, it is important to investigate the impact of drugs of abuse on HIV gene expression especially in brain cells, as brain is the target organ for both drugs of abuse and HIV. Cocaine is one of the most widely abused drugs in the United States, which both impair the normal functioning of brain cells and also activate HIV gene expression in central nervous system (CNS). As a result, HIV-infected individuals who abuse cocaine experience more severe and rapid onset of NeuroAIDS than non-abusing individuals. In this grant we will study the molecular mechanisms involved in the regulation of HIV gene expression and replication by cocaine in two primary macrophage cells, microglial (from brain) and peripheral macrophage (MDMs from PBMCs). Precisely, we will test the hypothesis that cocaine induces HIV replication by facilitating the recruitment of P-TEFb at HIV LTR via enhancing the phosphorylation of Histone H3 at serine 10 residue and through activation of specific transcription factors such as NF-kB and AP-1. These modifications ultimately contribute to more rapid deterioration of immune and nervous system, which is quite prevalent in drug addict HIV patients. Broader Impact: This work is expected to lead towards the discovery of new underlying molecular pathways, which could direct towards the new therapeutic strategies to address several adverse disease outcomes due to aberrant proviral gene expression and replication in drug addict HIV patients.